Field of the Invention
The invention relates generally to novel IL-17 antagonist antibodies and their use in the diagnosis or treatment of IL-17 mediated diseases.
Background
Interleukin-17 (“IL-17”), also known as IL-17A and CTLA-8, is a pro-inflammatory cytokine that stimulates secretion of various other cytokines in a variety of cell types. For example, IL-17 can induce IL-6, IL-8, G-CSF, TNF-α, IL-1β, and IFN-γ, as well as numerous chemokines and other effectors. See, e.g., Gaffen, S. L., Arthritis Research & Therapy 6: 240-247 (2004).
IL-17 is expressed by TH17 cells, which are involved in the pathology of inflammation and autoimmunity. It is also expressed by CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages and dendritic cells. IL-17 and Th17 are linked to pathogenesis of diverse autoimmune and inflammatory diseases, but are essential to host defense against many microbes, particularly extracellular bacteria and fungi. IL-17 can form homodimers or heterodimers with its family member, IL-17F. IL-17 binds to both IL-17 RA and IL-17 RC to mediate signaling. IL-17, signaling through its receptor, activates the NF-κB transcription factor, as well as various MAPKs. See, e.g., Gaffen, S., Nature Rev. Immunol. 9: 556-567 (2009).
IL-17 can act in cooperation with other inflammatory cytokines such as TNF-α, IFN-γ, and IL-1β to mediate pro-inflammatory effects. See, e.g., Gaffen, S. L., Arthritis Research & Therapy 6: 240-247 (2004). Increased levels of IL-17 have been implicated in numerous diseases, including rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, Crohn's diseases, allograft rejection, psoriasis, angiogenesis, atheroscloerosis, and multiple sclerosis. See, e.g., Gaffen, S. L., Arthritis Research & Therapy 6: 240-247 (2004); US Publ. No. 2008/-0269467 A1, published Oct. 30, 2008; Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162.
IL-17 and IL-17-producing TH17 cells have recently been implicated in certain cancers, Ji and Zhang, Cancer Immunol Immunother 59: 979-987 (2010). For example, IL-17-expressing TH17 cells were shown to be involved in multiple myeloma, Prabhala et al., Blood, online DOI 10.1182/blood-2009-10-246660, Apr. 15, 2010, and to correlate with poor prognosis in patients with HCC, Zhang et al., J. Hepatology 50: 980-89 (2009). Also, IL-17 was found to be expressed by breast-cancer-associated macrophages, Zhu et al., Breast Cancer Research 10:R95 (2008). More recently, the inventors showed that IL-17 antibodies are able to act on primary tumors and metastases in various kinds of cancer (see WO 2011/141823).
Accordingly, antibodies against IL-17 are useful tools for the diagnosis and/or treatment of a large panel of diseases. Novel antibodies against IL-17 with specific and advantageous properties are therefore required.